Carrimycin is a new derivative of spiramycin developed by adopting genetic engineering technology, which is originally named biotechspiramycin and formerly named biotechmycin [Patent No.: ZL97104440.6]. According to the “Rules for Chinese Approved Drug Names”, and upon technical review and confirmation of Chinese Pharmacopoeia Commission, the Chinese generic name of biotechspiramycin is changed to carrimycin.
Carrimycin is a fermentation product of genetically-engineered bacteria. The chemical structure of carrimycin mainly comprises 4″-isovalerylspiramycin, including 4″-isovalerylspiramycin I, II, III, and about 6 kinds of 4″-hydroxy acylated spiramycin, so the chemical name is 4″-acylspiramycin. Chemical structural form a of main component of carrimycin is as shown in form a (1):
                in which:        
RR′Isovalerylspiramycin IHCOCH2CH(CH3)2Isovalerylspiramycin IICOCH3COCH2CH(CH3)2Isovalerylspiramycin IIICOCH2CH3COCH2CH(CH3)2
Carrimycin is a 16-membered ring macrolide antibiotic, which inhibits the protein synthesis by combining with ribosome of bacterium.
In vitro test results show that carrimycin is effective against gram-positive bacteria, especially some drug-resistance bacteria such as β-lactam resistance staphylococcus aureus and erythrocin-resistance staphylococcus aureus, and has no significant cross drug resistance with similar drugs. Meanwhile, carrimycin has antibacterial activity for mycoplasma and chlamydia, as well as some gram-negative bacteria, good antibacterial activity and tissue permeability for epidemic toxoplasm and legionella, and still has potential immunoregulation function. The antibacterial activity in vivo is much better than that in vitro (ZL200310122420.9). Clinical research shows that by taking carrimycin tablets 0.2-0.4 mg everyday for 5˜7 days, it is suitable for treating acute bacterial pharyngitis and acute suppurative tonsillitis caused by pyogenic streptococcus; bacterial nasosinusitis and acute bronchitis caused by sensitized bacteria; mild pneumonia caused by streptococcus pneumonia, haemophilus influenza and mycoplasma pneumonia; nongonoccal urethritis caused by mycoplasma and chlamydia; infectious diseases such as skin and soft tissue infection, periodontitis and otitis media caused by sensitized bacteria. The total effective rate is 92.68%. Carrimycin is safe and effective.
Pharmacokinetics study shows that active components of carrimycin are mainly isovalerylspiramycin I, II and III. Carrimycin quickly metabolizes to spiramycin in vivo. According to AUC0-t of parent drug isovalerylspiramycin I, II and II and active metabolite spiramycin I, II and III, the absolute bioavailability by oral administration is 91.6% averagely. It is reported that the absolute bioavailability of spiramycin by oral administration is 30˜40% (Frydman A M et al J Antimicrob Chemother. 1988, 22 (suppl B):93-103). It shows that the isovalerylspiramycin significantly improves the bioavailability of active component spiramycin. Single dose carrimycin is eliminated slowly. T1/2 is between 23˜27 hours.
Researches on the active components of carrimycin show that a plurality of chiral carbon atoms exists in the molecular structure of active components of carrimycin: isovalerylspiramycin I, II and III. Chirality is a basic attribute of three-dimensional body and one of the essential attributes of nature. Biological macromolecules including protein, polysaccharide, nucleic acid and enzyme as important basis of vital movement often have important physiological functions. Chiral drug is a pair of enantiomers of material object and mirror image obtained after molecular structure of drug is introduced into the chiral center. These enantiomers are basically the same regarding physicochemical properties but different in optical rotation. The enantiomers are respectively named R-type (dextrorotatory) or S-type (sinistral), and racemic. In recent 20 years, as pharmaceutical research is more intensive, it has been proved that the difference of drug enantiomer's affinity with receptor caused by the difference of drug enantiomer's stereoselectivity leads to great difference in pharmacological action. Enantiomer with high activity among chiral drugs is called eutomer; while the one with low or no activity is called distomer. In many cases, the distomer not only has no pharmacological action, but also offset that of eutomer. Sometimes, severe toxic side reactions occur, showing the complexity of difference in pharmacological function and determining great difference in the therapeutic index of single enantiomer and the racemate thereof. For example, the curative effect of well-known DL-(+−) syntomycin is half of D (−) chloramphenicol; the pharmaceutical activity of propranolol L-isomer is 100 times larger than that of D-isomer; (−) adanon is a strong painkiller while (+) is non-effective. There is also difference in toxicity. For example, the two enantiomers of thalidomide have similar sedation for mice, but only S (−) isomer and metabolin thereof have embryotoxin and teratogenesis; ketamine is a widely used anaesthetic and analgesic, but has side effects such as hallucinating. Studies show that S(+) is 3˜4 times more effective than R(−) and toxic side effects have something to do with the latter. The great difference of chiral drug's curative effect has promoted the research and development of chiral drugs and the development separation analysis. By using “chiral” technology, we can remove those with no effect or toxic side effects from drugs effectively and produce pure chiral drugs with single and oriented structure, thus making more pure pharmaceutical ingredients, further quickening curative effect and shortening the course of treatment. Therefore, research on chiral drugs has become one of the new methods for new medicine research worldwide. National governments and pharmaceutical enterprises have invested heavily in fields such as preparations of chiral drug, chiral materials and chiral intermediate for research and development, for the purpose of seizing dominance of chiral pharmacy market. Beside, with continuous improvement of chiral technology, especially the fast and wide use of liquid chromatography, the separation analysis and determination of enantiomers of chiral drugs are promoted. Chiral drugs of single enantiomer have been widely used.
Through a lot of researches on whether carrimycin has optical activity too, the inventor is pleasantly surprised to find that by adjusting and optimizing the culturing and fermentation conditions, the inventor accidently gets a levocarrimycin with optical rotation, which has better anti-infection activity. Therefore, the present invention provides levocarrimycin, preparation methods thereof and uses in preparing drugs for preventing and treating infectious diseases.